We propose to continue and expand our previous investigations on the normal phagolysosomal system of the retinal pigment epithelium (RPE) in the phagocytosis of the rod-outer segments (ROS), their intracellular digestion, and the formation of residual bodies. Malfunction imposed on this normal phagocytic-lysosomal process will be examined in a number of inducded or inherited retinal degenerations in animals. Each animal model provides insight into one or more steps of the normal physiologic pathway, by providing malfunctions or pathologic events which ultimately may lead to loss of phagocytic capability, or may interrupt the intracellular digestive process, or may result in accumulation of normal or altered residual bodies. We will compare and contrast these studies on inherited retinal degenerations with studies on the normal retina of the rat, dog and bovus. Isolated and purified residual bodies (ceroid and lipofuscin) injected into the albino rabbit eye have been recently shown to be highly cytotoxic. We intend to define the nature and properties of the toxic substances in these residual bodies and trace their source in various retinal degenerations characterized by the accumulation of residual bodies. Among the inherited retinal degenerations available to our laboratory, the most promising is an English setter model of Batten's disease, a neuronal-retinal ceroid storage disorder. With these dogs, a resource unique to our laboratory, we have undertaken studies to provide new information on the biochemical defect among the lysosomal and peroxidative enzymes of peripheral leukocytes and tissues in this disorder. A number of new biochemical techniques have been developed, including specific methods for dissecting purifying and fractionating small samples of RPE into subcellular fractions suitable for in depth biochemical studies. We will identify the essential factors (enzymes, inhibitors, cations, or other chemical elements) that show significant changes during development and the progressive increase in cytotoxicity of residual bodies during the course of these diseases and in normal aging.